CH620420A5 - Process for separating the antipodes of 4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-3-carboxylic acids or of the racemic 1-(p-nitrophenyl)-2-aminopropane-1,3-diol - Google Patents

Description

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PATENT CLAIMS 1. Method for separating the antipodes of the racemic 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula

COOH

0

in which R is C 1-4 -alkyl, or of the racemic threo-1- (p-nitro-phenyl) -2-aminopropane-1,3-diol, characterized in that one with any of the enantiomers of the two compounds in aqueous Medium resolves the other race-mixed compound, whereby if (+) - threo-l- (p-nitro-phenyl) -2-aminopropane-1,3-diol or (-) - 4H- Pyrido (l, 2a) pyrimidine-3-carboxylic acid of the general formula I, the salt of (-) - 4H-pyrido (l, 2a) py-rimidin-3-carboxylic acid with (+) - threo-l- (p-nitro -phenyl) -2-aminopropane-l, 3-diol and, if (-) - threo-l- (p-nitro-phenyl) -2-aminopropane-l, 3-diol or ( +) - 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the general formula I, the salt of (+) - 4H-pyrido (l, 2a) pyrimidine-3-carbonic acid with (-) - threo-l - (p-Nitro-phenyl) -2-aminopropane-1,3-diol excretes in crystalline form; the crystals which have separated out are separated off by filtration, and by adjusting the pH of the mother liquor, the previously unresolved racemic 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula I precipitates and is filtered off, then the filtrate is mixed with a water-immiscible one Solvent extracted, the extract evaporated, leaving the antipode of the 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid component of the crystalline precipitated salt and by alkalizing the aqueous solution any threo-l- (p-nitro- phe-nyl) -2-aminopropane-l, 3-diol antipode excretes in crystalline form; the diastereomer salt precipitated in crystalline form dissolves in water, the pH of the solution is adjusted to 2 with acid, the solution is extracted with a water-immiscible solvent, the extract is evaporated, the 4H-pyrido (l, 2a) pyrimidine -3-carboxylic acid antipode remains; the aqueous solution is alkalized and the excreted threo-l- (p-nitro-phenyl) -2-aminopropane-1,3-diol antipode is separated off by filtration.

2. The method according to claim 1, characterized in that the racemic 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the general formula I with a threo-l- (p-nitro-phenyl) -2-amino -propane-1,3-diol antipodes in an aqueous medium, which separates the excreted diastereomer salt and from this releases the optically active 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula I, which in the Solution remaining other diastereomer salt from the salt of racemic 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid separated by pH adjustment and from this the optically active 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid antipodes of formula I isolated.

3. The method according to claim 1, characterized in that the racemic 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula I 6-methyl-4-oxo-6,7,8,9-tetrahydro- 4H-py-rido (1,2a) pyrimidine-3-carboxylic acid was used.

4. The method according to claim 1, characterized in that the molar ratio between the 4H-pyrido (l, 2a) py-rimidin-3-carboxylic acid of the general formula I or the threo-l- (p-nitro-phenyl) -2 -amino-propane-l, 3-diol antipodes and the racemic 4H-pyrido (l, 2a) pyrimidine carboxylic acid of the formula I or the racemic threo-l- (p-nitro-phenyl) -2-amino- propane-l, 3-diol between 0.3 and 1.2.

5. The method according to any one of claims 1-4, characterized in that the pH in the reaction of 4H-pyrido (l, 2a) py-rimidin-3-carboxylic acid of the formula I or threo-l- used as a resolving agent (p-nitro-phenyl) -2-aminopropane-l, 3-diol with the racemic 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid or threo-l- (p-nitro-phenyl) - 2-amino-propane-l, 3-diol between 5 and 8, suitably 6.5 and 7.

6. The method according to any one of claims 1-5, characterized in that the pH is adjusted with lye, expediently with ammonium hydroxide, or acid, expediently with hydrochloric acid.

7. The method according to any one of claims 1-6, characterized in that in the case of a molar ratio of 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of formula I to threo-l- (p-nitro-phenyl) - 2-amino-propane-l, 3-diol of 1: 1 warms the reaction mixture, in the case of a different molar ratio the threo-l- (p-nitro-phenyl) -2-aminopropane-l, 3-diol in an aqueous acid, suitably in hydrochloric acid, dissolves at pH 5.5, the 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of formula I in an alkali, expediently in ammonium hydroxide, dissolves at pH 7 and the two solutions combined or to the latter an acid addition salt, advantageously the hydrochloride of threo-l- (p-nitro-phenyl) -2-ami-no-propane-l, 3-diol, in solid form.

8. The method according to any one of claims 1-7, characterized in that the diastereomer salts of 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid with threo-l- (p-nitro-phe-nyl) -2 -amino-propane-l, 3-diol in solution or after dissolving with excess acid, advantageously with hydrochloric acid, decomposed in such a way that the pH is adjusted to a maximum of 4, expediently 2, then the excreted unresolved 4H -Pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula I is separated off by filtration and resolved anew.

9. The method according to any one of approached 1-8, characterized in that the antipodes of 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula I or threo-l- ( p-Nitro-phenyl) -2-amino-propane-1,3-diols used again for the resolvation.

It is known from British PS 1,358,414 that the enantiomers of (±) -3-carboxy-4-oxo-6-methyl-6,7,8,9-te-trahydro-4H-pyrido (l, 2a ) pyrimidins can be separated from one another by means of an optically active base used as a resolving agent. Kinin is mentioned as an example and the use of phenylethylamine is supported by examples. According to the description, the resolvation is carried out using (+) - phenylethylamine. The procedure consists of the following:

The mixture of the racemic compound and the (+) - phenylethylamine in a molar ratio of 1: 1 is heated in 95% dimethoxyethane, left to stand at room temperature, filtered off and the salt of the crude (-) - isomer - (+) - phenylethylamine recrystallized three times. The (~) isomer is then released from this salt (25.3%).

The mother liquor is evaporated, the rest is taken up in water and the mixture of the racemic and (+) - isomer form is precipitated in a molar ratio of 80:20 with hydrochloric acid, then the crude (+) - isomer is extracted from the water. Furthermore, the extracted (+ j-crude isomer in ethyl acetate is converted into a salt with (-) - phenyl-ethylamine and the salt obtained is recrystallized several times. The (+) - isomer is released in water using hydrochloric acid ( 13.0%).

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The main disadvantage of the process is that both phenylethylamine isomers are required to prepare the isomers. If the intention is only to prepare the (-) - isomer, the use of the (H -) - phenylethylamine is sufficient, but if the purpose of the (+) - isomer is to produce, the (+) - like the (-) - phenyl-ethyl-amine can be used. The solvent and the resolving agent are expensive and the yield is poor. The method does not provide any information about the reuse of the regenerated substances and the regenerability of the resolving agent.

Surprisingly, it was found that the racemic 4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2a) pyrimidine-3-carboxylic acids of the general formula I, in which

R denotes an alkyl group with Ci_4,

can be resolved with both optical isomers of threo-l- (p-nitro-phenyl) -2-aminopropane-1,3-diol (i.e. "aminodiol") in an aqueous medium with good yield. A special meaning of this knowledge is to be seen in

that the L - (+) - aminodiol has so far been obtained as a hardly used waste product in the industrial production of chloro-amphenicol. The resolvation can be carried out with both enantiomers; the yield of the resolving agent regeneration is about 90%. The unresolved portion can be regenerated approximately quantitatively from the racemic compound and used again for the resolvation. It is thus possible to resolve the racemic compound with an approximately quantitative yield.

It is also surprising that the racemic aminodiol can also be resolved, both with the (+) - and the (-) - 4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine -3-carboxylic acids of formula I. In this way it is possible to resolve the two racemic compounds, namely the (+) - 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acids of formula I with the unusable L ~ (+) - isomer of the aminodiol and simultaneously the racemic aminodiol can be resolved with the unusable isomer of the acid mentioned. Both options have the advantages already mentioned.

From the point of view of industrial implementation, it is noteworthy that the resolvation can in any case be carried out in an aqueous medium. The resolving agent is a racemic compound, its molar ratio can be between 0.3 and 1.2. The resolvation can be carried out by introducing the racemic compound and the optical antipode used for the resolvation, adding water to the mixture, heating until it dissolves and then bringing the pH to 5.5-7.5, expediently to 6.5- 7 sets. An acid or base is used to adjust the pH. One can also proceed in such a way that a neutral salt of the racemic compound or the resolving agent is dissolved in the water [expedient for neutralization in the case of the 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid amminium hydroxide solution and in the case of the aminodiol hydrochloric acid] and pour the two solutions together. According to another process variant, one can proceed in such a way that the neutral aqueous solution of the racemic 4H-pyrido (1,2a) pyrimidine-3-carboxylic acids of formula I with the hydrochloride of one of the two isomers of the optically active aminodiol or another neutral salt in solid form. The following salts separate themselves from the solutions thus obtained in crystal form or after inoculation:

1. in the case of the reaction of (±) -4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula I with L - (+) - threo-aminodiol, the salt of (-) - 4H-pyrido ( l, 2a) pyrimidine-3-carboxylic acid with L - (+) -threo- «aminodiol»,

2. in the case of the reaction of (+) - 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid with D - (-) - threo-aminodiol, the salt of (+) - 4H-pyrido (l, 2a ) pyrimidine-3-carboxylic acid with D - (-) - threo- «aminodiol»,

3. in the case of the reaction of (±) -threo-aminodiol with (-) - 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid, the salt of (-) - 4H-pyrido (l, 2a) pyrimidine-3 -carboxylic acid with L - (+) - threo- «aminodiol»,

4. in the case of the reaction of (+) - threo-aminodiol and the (+) - 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the general formula I, the salt of (+) - 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid with D - (-) - threo- «aminodiol».

Both the resolved isomer and the resolving agent can be released from the salts obtained as follows: one of the salts mentioned is dissolved in water and the pH of the solution is adjusted to 2. The possibly precipitated racemic 4H-pyrido (l, 2a) pyrimidine-3-carbonic acid of the formula I is filtered off and the filtrate is extracted with chloroform, the chloroform phase is evaporated, the optical antipode of the 4H-pyrido (l, 2a) pyrimidine-3-kar-bonic acid of formula I remains. The pH of the mother liquor is first adjusted to 5.5 and then the amount of caustic, expediently ammonium hydroxide, equivalent to the racemic aminodiol content is added. The precipitated racemic aminodiol is separated off by filtration; after further addition of ammonium hydroxide, the optically active aminodiol separates out and is separated off by filtration.

The enantiomers of the crude 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acids of the formula I can be purified via their salts formed with the corresponding optically active aminodiols and from these the 4H-pyrido (l, 2a) pyrimidine-3-car- bonic acid antipode are released in pure form or by fractional precipitation from their aqueous, neutral salt solution and removal of the excreted racemic 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid by filtration, subsequent extraction from the aqueous solution with a water miscible solvents, expediently cleaned with chloroform, and evaporation of the chloroform phase.

Because of the above, the resolvation of the two racemic compounds [i.e. H. the 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid of the formula I and the aminodiol] with their mutual antipodes enable the following process variants. One of these variants is illustrated in Fig. 1.

The optically active 4H-pyrido (l, 2a) pyrimidine-3-carboxylic acids can be used as a resolving agent in synthesis in the pharmaceutical industry, on the one hand, as a useful intermediate, in the synthesis of compounds that act on the central nervous system, and those with anti-inflammatory agents , anti-arteriosclerotic and antiplatelet activity, can be used.

example 1

123.0 g of racemic 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2a) pyrimidine-3-carboxylic acid are suspended in 250 ml of water. The pH of the solution is concentrated with aq. NH4OH solution set to 7. 88.0 g of solid hydrochloride of L - (+) - threo-l- (p-nitro-phenyl) -2-aminopropane-1,3-diol are added to the solution obtained. After the introduction of a seed crystal, crystals are separated from the solution. The reaction mixture is left overnight at room temperature, then the crystals which have separated out are filtered off and washed with water.

137.8 g of soaking-wet salt of (-) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carbon

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Acid obtained with L - (+) - threo-l- (p-nitro-phenyl) -2-aminopropane-1,3-diol.

The pH value of the aqueous filtrate is adjusted with aqueous conc. HCl solution set to 4 and allowed to stand between 9 and 5 ° C for one hour. The crystals which have separated out are filtered off, washed with water and dried. 61 g of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridone (1,2a) pyrimidine-3-carboxylic acid are obtained.

Melting point: 134 ° C.

[a] D20 = (+) 27 - (+) 35 ° c = 2, methanol.

The pH of the filtrate obtained is concentrated with further aqueous. HCl solution set to 2 and then shaken with 3x 150 ml chloroform. The combined chloroform extracts are dried over sodium sulfate, filtered off and evaporated. 23.0 g of (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid are obtained.

Melting point: 117 ° C.

[a] D20 = (+) 106 - (+) 110 ° c = 2, methanol.

137.8 g of the drenched salt of (-) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid with L - (+) - threo-l- (p-nitro-phenyl) -2-amino-propane-l, 3-diol are dissolved with heating in 900 ml of water, then the pH of the solution at 30 ° C with aqueous conc. HCl solution set to 2. The solution is extracted with 2x 150 ml chloroform. The combined chloroform phases are dried over sodium sulfate, filtered off and evaporated.

38.3 g of (-) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid are obtained.

Melting point: 116 ° C.

\ a.] D20 = (-) 90 ° c = 2, methanol.

The whole amount (38.3 g) of the substance obtained is concentrated in 80 ml of water with the addition of aqueous. NH4OH solution dissolved in such a way that the pH of the solution obtained is 7. Then 50 g of L - (+) - threo-l- (p-nitro-phenyl) -2-aminopropane-1,3-diol are added to the solution and the procedure is analogous to that described above.

30.2 g of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2a) pyrimidine-3-carboxylic acid are obtained.

Melting point: 119 ° C.

[u] D20 = (-) 110 ° c = 2, methanol.

Example 2

20.0 g racemic threo-l- (p-nitro-phenyl) -2-amino-pro-pan-l, 3-diol and 10.0 g (+) - 6-methyl-4-oxo-6.7 , 8,9-tetrahy-dro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid are dissolved in 70 ml of water at 70 ° C., then the solution obtained is cooled to 20 ° C. and left to stand overnight. The precipitated salt of (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid with D - (-) - threo-l- (p-Nitro-phenyl) -2-aminopropane-l, 3-diol is filtered off, covered with water and dissolved in four times the amount of water with heating, then the pH value with aqueous conc. NH4OH solution set to 9. The crystals which have separated out are filtered off. 5.6 g of D - (-) - threo-l- (p-Ni-tro-phenyl) -2-aminopropane-1,3-diol are obtained.

Melting point: 163 ° C.

[«] D20 = (-) 30 ° c = 2, in nHCl solution.

Example 3

The procedure is as in Example 2, with the difference that the resolvation with (-) - 6-methyl-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido (l, 2a) pyrimidine- 3-carboxylic acid is carried out. 5.7 g of L - (+) - threo-l- (p-nitro-phenyl) -2-ami-no-propane-1,3-diol are thus obtained.

Melting point: 163 ° C.

[«Lo20 = (+) 30 ° c = 2, in nHCl solution.

Example 4

42 g of racemic 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2a) pyrimidine-3-carboxylic acid are suspended in 80 ml of water and the pH of the mixture with aqueous conc . NH4OH solution set to 7. 25.5 g of hydrochloride of L - (+) - threo-l- (p-nitro-phenyl) -2-aminopropane-l, 3-diol are added in solid form and the solution at 20 ° C. Left at night. The crystals which have separated out are filtered off and washed with water. 29.5 g of salt of (-) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid with L - (+) - threo-l- (p-Ni-tro-phenyl) -2-aminopropane-1,3-diol are obtained.

[a \ D20 = (-) 47.5 ° - (-) 53 ° c = 2, methanol.

The crystalline substance is dissolved at 60 ° C in 280 ml of water and the pH with aqueous conc. Hydrochloric acid solution set to 2. 4.4 g of 6-methyl-4-oxo-6,7,8,9-te-trahydro-4H-pyrido (1,2a) pyrimidine-3-carboxylic acid separate out, which are separated off by filtration.

Melting point: 123 ° C.

Hd20 = (-) 60 ° c = 2, methanol.

The filtrate is extracted four times with 50 ml of chloroform. The combined chloroform solutions are dried over sodium sulfate, filtered and evaporated. 9.5 g of (+) - 6-methyl-4-oxo-6,7,8,9-tetrahy-dro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid melting at 118 ° C. are obtained.

[a] D20 = (+) 95 ° c = 2, methanol.

The salt of (-) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid with L - (+) - threo-l- ( p-Nitro-phenyl) -2-aminopropane-l, 3-diol, obtained in an amount of 29.5 g, is dissolved in 150 ml of water and the pH of the solution with aqueous conc. Hydrochloric acid solution adjusted to 4-4.5. The crystals which have separated out are filtered off. 14 g of salt of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid are obtained.

Melting point: 134.5 ° C.

[cc] D20 = (+) 25 ° c = 2, methanol.

The filtrate is extracted four times with 50 ml of chloroform. The combined chloroform phases are dried over sodium sulfate, filtered off and evaporated. 8.9 g (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2a) pyrimidine-3-carboxylic acid are obtained.

Melting point: 119 ° C.

[«] D20 = (+) 90 ° c = 2, methanol.

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